Lipids in infant formulas: Current and future innovations

Lipids in infant formulas are designed to mimic the composition of human milk and/or approximate the performance of the breastfed infant. Human milk lipids exhibit a complex, highly variable nature, varying by population, dietary intake, time of day, length of feeding and others. Continued understanding and characterization of human milk lipids has led to infant formula innovations aimed at a better comparison to human milk and/or improved dietary lipid utilization in the formula‐fed infant. The underlying aim of such innovation is the generation of outcomes as comparable to human milk feeding as possible. The present paper briefly reviews the current understanding of human milk lipid composition, with a focus on how this knowledge drives current and future innovations in the area of infant formula lipids.     

Visual acuity and erythrocyte docosahexaenoic acid status in breast-fed and formula-fed term infants during the first four months of life

It has been recognized that preterm infants have a more rapid development of visual acuity if fed human milk or a formula enriched with the long-chain polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA) compared to a standard formula devoid of LCPUFA. Few studies have addressed whether the same is also true in term infants. The aim of the present study was to follow visual acuity and fatty acid composition in red blood cells (RBC) for the first 4 mon of life in 17 breast-fed and 16 formula-fed term infants. The formula used did not contain LCPUFA, but contained 1.7 wt% α-linolenic acid, and the linoleic/α-linolenic acid ratio was 8.5. The increase in visual acuity measured by Teller acuity cards developed more rapidly in breast-fed infants compared to formula-fed infants (P<0.001). This was parallelled by a decrease in DHA of RBC in formulafed infants, and with a significantly lower level at two and four months as compared to breast-fed infants. The content of DHA in milk from the breast-feeding mothers was high compared to other Western countries. The difference in visual acuity between the two feeding groups could be due to differences in DHA status as reflected by the RBC levels, but other explanations are possible. Intervention studies are required to verify if development of visual acuity in term formula-fed infants is dependent on the DHA level of formula. Based on a presentation at the AOCS Annual Meeting & Expo in San Antonio, Texas, May 7–11, 1995.     

Evidence that palmitic acid is absorbed assn-2 monoacylglycerol from human milk by breast-fed infants

Milk fatty acids consist of about 20–25% palmitic acid (16∶0), with about 70% of 16∶0 esterified to thesn-2 position of the milk triacylglycerols. Hydrolysis of dietary triacylglycerols by endogenous lipases producessn-2 monoacylglycerols and free fatty acids, which are absorbed, reesterified, and then secreted into plasma. Unesterified 16∶0 is not well absorbed and readily forms soaps with calcium in the intestine. The positioning of 16∶0 at thesn-2 position of milk triacylglycerols could explain the high coefficient of absorption of milk fat. However, the milk lipase, bile salt-stimulated lipase, has been suggested to complete the hydrolysis of milk fat to free fatty acids and glycerol. These studies determined whether 16∶0 is absorbed from human milk assn-2 monopalmitin by comparison of the plasma triacylglycerol total andsn-2 position fatty acid composition between breast-fed and formula-fed term gestation infants. The human milk and formula had 21.0 and 22.3% of 16∶0, respectively, with 54.2 and 4.8% 16∶0 in the fatty acids esterified to the 2 position. The plasma triacylglycerol total fatty acids had 26.0±0.6 and 26.2±0.6% of 16∶0, and thesn-2 position fatty acids had 23.3±3.3 and 7.4±0.7% of 16∶0 in the three-month-old exclusively breast-fed (n=17) and formula-fed (n=18) infants, respectively. Marked differences were found in the plasma total and the 2 position phospholipid percentage of 20∶4ω6, i.e., 11.6±0.3 and 6.9±0.6 (total), 17.7±1.4 and 9.7±0.6 (sn-2 position) and percentage of 22∶6ω3, 4.6±0.3 and 2.1±0.3 (total), 5.6±0.6 and 2.0±0.2 (sn-2 position) for the breast-fed and formula-fed infants, respectively. These studies provide convincing evidence that 16∶0 is absorbed from human milk assn-2 monoacyl-glycerol. The metabolic significance of the differences in positional distribution of fatty acids in the plasma lipids of breast-fed and formula-fed infants is not known.     

Infant cerebellar gray and white matter fatty acids in relation to age and diet

There is little evidence as to the fatty acid composition of the cerebellum in infancy and it remains uncertain whether milk diet can influence its composition. We therefore examined cerebellar gray and white matter of infants less than 6 mon old who had died unexpectedly. The fatty acid content of 33 gray and 21 white matter specimens from infants born at term and 6 gray and 5 white matter specimens from pretern infants was assessed by gas chromatographic/mass spectrometric analysis. Infants were grouped according to whether they had received human or manufactured formula milk. Whereas cerebellar cortex docosahexaenoic acid (DHA, 22∶6n−3) concentrations were significantly lower (P<0.01) in the formula-fed than breast-fed infants, no differences existed between the term (n=10) and preterm (n=5) Scientific Milk Adaptation (SMA) formula-fed infants. Cerebellar white matter DHA concentrations were similarly lower (P<0.01) in the SMA formula-fed infants (n=8) than in an age-matched breast-fed group. Low concentrations of cerebellar white matter lignoceric (24∶0) and nervonic acid (24∶1n−9) in two 7-wk-old preterm infants appeared to correlated with postgestational rather than chronological age. Dietary long-chain polyunsaturated fatty acids particularly DHA, are probably essential for normal development of the infant cerebellum.     

Breast-fed infants achieve a higher rate of brain and whole body docosahexaenoate accumulation than formula-fed infants not consuming dietary docosahexaenoate

Docosahexaenoate (DHA) has been increasingly recognized as an important fatty acid for neural and visual development during the first 6 mon of life. One important point of controversy that remains is the degree to which adequate levels of DHA can be acquired from endogenous synthesis in infants vs. what should be provided as dietary DHA. We have approached this problem by a retrospective analysis of published body composition data to estimate the actual accumulation of DHA in the human infant brain, liver, adipose tissue, remaining lean tissue, and whole body. Estimating whether infants can synthesize sufficient DHA required comparison to and extrapolation from animal data. Over the first 6 mon of life, DHA accumulates at about 10 mg/d in the whole body of breast-fed infants, with 48% of that amount appearing in the brain. To achieve that rate of accumulation, breast-fed infants need to consume a minimum of 20 mg DHA/d. Virtually all breast milk provides a DHA intake of at least 60 mg/d. Despite a store of about 1,050 mg of DHA in body fat at term birth and an intake of about 390 mg/d α-linolenate (α-LnA), the brain of formula-fed infants not consuming DHA accumulates half the DHA of the brain of breast-fed infants while the rest of the body actually loses DHA over the first 6 mon of life. No experimental data indicate that formula-fed infants not consuming DHA are able to convert the necessary 5.2% of α-LnA intake to DHA to match the DHA accumulation of breast-fed infants. We conclude that dietary DHA should likely be provided during at least the first 6 mon of life.     

Lipid Metabolism Is Dysregulated before,during and after Pregnancy in a Mouse Model of Gestational Diabetes

The aim of the current study was to test the hypothesis that maternal lipid metabolism was modulated during normal pregnancy and that these modulations are altered in gestational diabetes mellitus (GDM). We tested this hypothesis using an established mouse model of diet-induced obesity with pregnancy-associated loss of glucose tolerance and a novel lipid analysis tool, Lipid Traffic Analysis, that uses the temporal distribution of lipids to identify differences in the control of lipid metabolism through a time course. Our results suggest that the start of pregnancy is associated with several changes in lipid metabolism, including fewer variables associated with de novo lipogenesis and fewer PUFA-containing lipids in the circulation. Several of the changes in lipid metabolism in healthy pregnancies were less apparent or occurred later in dams who developed GDM. Some changes in maternal lipid metabolism in the obese-GDM group were so late as to only occur as the control dams’ systems began to switch back towards the non-pregnant state. These results demonstrate that lipid metabolism is modulated in healthy pregnancy and the timing of these changes is altered in GDM pregnancies. These findings raise important questions about how lipid metabolism contributes to changes in metabolism during healthy pregnancies. Furthermore, as alterations in the lipidome are present before the loss of glucose tolerance, they could contribute to the development of GDM mechanistically.     

Comprehensive and quantitative profiling of lipid species in human milk,cow milk and a phospholipid‐enriched milk formula by GC and MS/MSALL

Here we present a workflow for in‐depth analysis of milk lipids that combines gas chromatography (GC) for fatty acid (FA) profiling and a shotgun lipidomics routine termed MS/MS^ALL for structural characterization of molecular lipid species. To evaluate the performance of the workflow we performed a comparative lipid analysis of human milk, cow milk, and Lacprodan^® PL‐20, a phospholipid‐enriched milk protein concentrate for infant formula. The GC analysis showed that human milk and Lacprodan have a similar FA profile with higher levels of unsaturated FAs as compared to cow milk. In‐depth lipidomic analysis by MS/MS^ALL revealed that each type of milk sample comprised distinct composition of molecular lipid species. Lipid class composition showed that the human and cow milk contain a higher proportion of triacylglycerols (TAGs) as compared to Lacprodan. Notably, the MS/MS^ALL analysis demonstrated that the similar FA profile of human milk and Lacprodan determined by GC analysis is attributed to the composition of individual TAG species in human milk and glycerophospholipid species in Lacprodan. Moreover, the analysis of TAG molecules in Lacprodan and cow milk showed a high proportion of short‐chain FAs that could not be monitored by GC analysis. The results presented here show that complementary GC and MS/MS^ALL analysis is a powerful approach for characterization of molecular lipid species in milk and milk products. Practical applications : Milk lipid analysis is routinely performed using gas chromatography. This method reports the total fatty acid composition of all milk lipids, but provides no structural or quantitative information about individual lipid molecules in milk or milk products. Here we present a workflow that integrates gas chromatography for fatty acid profiling and a shotgun lipidomics routine termed MS/MS^ALL for structural analysis and quantification of molecular lipid species. We demonstrate the efficacy of this complementary workflow by a comparative analysis of molecular lipid species in human milk, cow milk, and a milk‐based supplement used for infant formula. A workflow for milk lipid analysis based on combined gas chromatography and high‐resolution shotgun lipidomics. In‐depth structural characterization and quantification of molecular lipid species in milk and milk products.     

Dietary nucleotides do not alter erythrocyte long-chain polyunsaturated fatty acids in formula-fed term infants

There have been conflicting reports regarding the effectiveness of dietary nucleotides (NT) to regulate tissue desaturases and hence stimulate accumulation of both n−6 and n−3 long-chain polyunsaturated fatty acids (LCPUFA). The aim of this study was to examine the effect of NT-supplemented cow's milk-based formula on erythrocyte phospholipid FA status in a large randomized controlled trial involving a well-nourished infant population born at term. Formula-fed infants were allocated to control formula with an innate level of NT at 10 mg/L (n=102), or formula fortified with NT at 34 mg/L (n=98). A parallel group of breastfed infants was included as a reference. Peripheral blood samples were collected by venipuncture at 7 mon of age and erythrocyte phospholipid FA determined by capillary GC. Erythrocyte LCPUFA levels did not differe between the NT-supplemented and control formula groups and were reduced in both groups compared with breastfed infants. We conclude that there is no induction of LCPUFa accumulation in erythrocyte phospholipids of term, formula-fed infants following 7 mon of NT supplementation.     

Kidney Damage Caused by Obesity and Its Feasible Treatment Drugs

The rapid growth of obesity worldwide has made it a major health problem, while the dramatic increase in the prevalence of obesity has had a significant impact on the magnitude of chronic kidney disease (CKD), especially in developing countries. A vast amount of researchers have reported a strong relationship between obesity and chronic kidney disease, and obesity can serve as an independent risk factor for kidney disease. The histological changes of kidneys in obesity-induced renal injury include glomerular or tubular hypertrophy, focal segmental glomerulosclerosis or bulbous sclerosis. Furthermore, inflammation, renal hemodynamic changes, insulin resistance and lipid metabolism disorders are all involved in the development and progression of obesity-induced nephropathy. However, there is no targeted treatment for obesity-related kidney disease. In this review, RAS inhibitors, SGLT2 inhibitors and melatonin would be presented to treat obesity-induced kidney injury. Furthermore, we concluded that melatonin can protect the kidney damage caused by obesity by inhibiting inflammation and oxidative stress, revealing its therapeutic potential.     

Dietary modifications of animal fats: status and future perspectives

The purpose of modifying animal fats is to produce high quality products, which meet the dietary recommendations for a reduced intake of fat in the human diet, notably that of certain saturated fatty acids and cholesterol, and an increased intake of mono- (MUFA) and polyunsaturated fatty acids (PUFA) in order to minimize the risk for obesity, cancer, cardiovascular, and other life-style diseases. The body fat of farm animals is partly synthesized from dietary carbohydrates, partly from dietary fatty acids. In monogastric animals, preruminants and poultry PUFAs are readily absorbed and deposited in the edible parts of the body and incorporated into egg yolk lipids. In ruminants, however, PUFAs are hydrogenated to mainly saturated fatty acids by the rumen microorganisms with some formation of MUFAs, trans-, odd-, branched chain, and conjugated fatty acids. The latter fatty acids are absorbed, deposited in adipose and muscle tissue and incorporated into milk lipids, unless dietary PUFAs are protected against hydrogenation. Thus, it is relatively easy to change the fatty acid composition of pork, poultry meat, lamb, and veal, whereas beef and milk can only be enriched significantly with PUFAs by manipulation. Products enriched with PUFAs are, however, prone to oxidation, and enrichment with antioxidants, notably with dietary vitamin E, is necessary in order to prevent the risk of oxidative damage.     

Melatonin in Early Nutrition: Long-Term Effects on Cardiovascular System

Breastfeeding protects against adverse cardiovascular outcomes in the long term. Melatonin is an active molecule that is present in the breast milk produced at night beginning in the first stages of lactation. This indoleamine appears to be a relevant contributor to the benefits of breast milk because it can affect infant health in several ways. The melatonin concentration in breast milk varies in a circadian pattern, making breast milk a chrononutrient. The consumption of melatonin can induce the first circadian stimulation in the infant’s body at an age when his/her own circadian machinery is not functioning yet. This molecule is also a powerful antioxidant with the ability to act on infant cells directly as a scavenger and indirectly by lowering oxidant molecule production and enhancing the antioxidant capacity of the body. Melatonin also participates in regulating inflammation. Furthermore, melatonin can participate in shaping the gut microbiota composition, richness, and variation over time, also modulating which molecules are absorbed by the host. In all these ways, melatonin from breast milk influences weight gain in infants, limiting the development of obesity and comorbidities in the long term, and it can help shape the ideal cellular environment for the development of the infant’s cardiovascular system.     

Tolerance of a standard intact protein formula versus a partially hydrolyzed formula in healthy, term infants

Background  

Parents who perceive common infant behaviors as formula intolerance-related often switch formulas without consulting a health professional. Up to one-half of formula-fed infants experience a formula change during the first six months of life.     

Mechanisms of Melatonin in Obesity: A Review

Obesity and its complications have become a prominent global public health problem that severely threatens human health. Melatonin, originally known as an effective antioxidant, is an endogenous hormone found throughout the body that serves various physiological functions. In recent decades, increasing attention has been paid to its unique function in regulating energy metabolism, especially in glucose and lipid metabolism. Accumulating evidence has established the relationship between melatonin and obesity; nevertheless, not all preclinical and clinical evidence indicates the anti-obesity effect of melatonin, which makes it remain to conclude the clinical effect of melatonin in the fight against obesity. In this review, we have summarized the current knowledge of melatonin in regulating obesity-related symptoms, with emphasis on its underlying mechanisms. The role of melatonin in regulating the lipid profile, adipose tissue, oxidative stress, and inflammation, as well as the interactions of melatonin with the circadian rhythm, gut microbiota, sleep disorder, as well as the α7nAChR, the opioidergic system, and exosomes, make melatonin a promising agent to open new avenues in the intervention of obesity.     

Breast feeding in different income classes in the Municipality of S?o Paulo

The relationship between breast feeding and socioeconomic factors in children below 2 from different social classes in Sao Paulo, Brazil is analyzed. Of a total 200 children, 46 were malnourished and 31 belonged to the lower socioeconomic classes. 39% of mothers from the lower income families breastfed for 6 months, as compared to 13% of mothers from families with higher incomes 18% and 36% of mothers from the 2 classes did not breastfeed; mothers from the middle class breastfed for an average 28 days. The problem of protein-calorie malnutrition in young children is a growing one in Brazil, even in a relatively rich city such as Sao Paulo; one of the factors responsible for this problem is undoubtedly early weaning. Reasons given for early weaning in a group of 351 mothers were deficient amount of milk (49.6%), medical advice (11.1%), "bad" milk (14.3%), and only 1.4% because of occupation outside of the home. When interviewed about their opinion on the best type of milk for infants, 45% out of a group of 500 mothers indicated artificial milk, 37% maternal milk, and 16.2% cow's milk. Out of 492 mothers, 77% had 4 prenatal visits at a public health center, 11% had no prenatal visits, and 12% had 1-3 visits. Prenatal care does not influence attitude in favor of breast feeding; 45.5% of mothers who had not had any prenatal care breastfed for 6 months or more, as compared to 20% of those with 1-3 visits, and 17.5% of those with 4 visits. Those who delivered in a hospital tended to breastfeed more than those who delivered at home. It is obvious that not only mothers but health workers as well must be educated on the importance of breast feeding to fight infant malnutrition in Brazil.     

Factors that influence the antirachitic value of milk for infant feeding

Summary It is quite evident from the foregoing that both breast milk and cow’s milk contain variable amounts of calcium, phosphorus and Vitamin D. Since these factors are of primary importance for promoting satisfactory bone growth it is apparent that neither breast milk nor cow’s milk can always be depended upon to protect infants against rickets. Hence it has become a quite general practice to supplement breast milk with orange juice and cod liver oil or other sources of the necessary vitamins, and modify cow’s milk by adding materials which supply the desired minerals, vitamins and calories. Accordingly the need for careful supervision of the diet of the infant has become very generally accepted, particularly as the infant’s dietary is very restricted and its margin of safety as regards its nutritive requirements is lower than during later life.     

Longitudinal Evolution of the Concentration of Gangliosides GM3 and GD3 in Human Milk

It has been reported that dietary gangliosides may have an important role in preventing infections and in brain development during early infancy. However, data related to the evolution of their concentration over the different stages of lactation are scarce. Liquid chromatography coupled with electrospray ionization high resolution mass spectrometer (LC/ESI‐HR‐MS) has been optimized to quantify the two major ganglioside classes, i.e., aNeu5Ac(2‐8)aNeu5Ac(2‐3)bDGalp(1‐4)bDGlcp(1‐1)Cer (GD3) and aNeu5Ac(2‐3)bDGalp(1‐4)bDGlcp(1‐1)Cer (GM3) in human milk. Gangliosides were extracted using chloroform and methanol, further purified by solid‐phase extraction and separated by reversed‐phase liquid chromatography. Repeatability, intermediate reproducibility, and recovery values were assessed to validate the method. In human milk, GD3 and GM3 could be quantified at the level of 0.1 and 0.2 μg/mL, respectively, with relative standard deviation of repeatability [CV(r)] and intermediate reproducibility [CV(iR)] values ranging from 1.9 to 15.0 % and 1.9 to 22.5 %, respectively. The described method was used to quantify GD3 and GM3 in human milk samples collected from 450 volunteers between 0 and 11 days and at 30, 60 and 120 days postpartum, providing for the first time the concentration of these minor lipids in a large cohort. The content of total gangliosides ranged from 8.1 and 10.7 μg/mL and the mean intake of gangliosides in infants 30, 60 and 120 days postpartum could be estimated at about 5.5, 7.0 and 8.6 mg of total gangliosides per day, respectively, when infants were exclusively breastfed.     

Is dietary docosahexaenoic acid essential for term infants?

There is a need to determine whether there is a dietary requirement for docosahexaenoic acid (DHA, 22∶6ω3) by term infants to achieve their full developmental potential. Studies of brain fatty acid composition have demonstrated that infants who were breast fed have greater levels of cerebral cortex DHA than infants who were formula fed, suggesting that DHA in the cerebrum is dependent on a supply in the diet. Some physiological studies report that electrophysiological and behavioral assessments of visual function are improved in breast-fed infants relative to those fed formula, and that this is related to the level of DHA in their erythrocytes, whereas other studies demonstrate equivalent visual function between breast-and formula-fed infants. However, randomized studies of DHA supplementation of infant formula demonstrate that the visual function of formula-fed infants can be improved to breast-fed levels by adding DHA to formula. Further work is necessary to establish if there are long-term benefits of dietary DHA to the term infant. Based on a presentation at the AOCS Annual Meeting & Expo in San Antonio, Texas, May 7–11, 1995.     

The simultaneous separation and quantitation of human milk lipids

A protocol using a dry column method was modified for the extraction of total lipids and the simultaneous separation and quantitation of neutral and polar lipids in human milk. The triacylglycerol, cholesterol, phospholipid and vitamin E contents of the lipid extracts were determined and compared with lipids extracted using a modified Folch procedure. Good precision for the extraction of neutral, polar and total lipids, as well as the different lipid classes, was demonstrated. No significant differences were found between the two methods with respect to the amount of cholesterol, phospholipid, total lipid or vitamin E extracted, thus validating the method as an extraction technique. We discuss the relationship between vitamin E and the three major milk lipids as an indicator of the vitamin's place of origin in the mammary gland. Our findings do not support the idea that vitamin E in mature milk has its original location in the apical membrane. Scientific Contribution No. 1254, Storrs Agricultural Experiment Station, University of Connecticut, Storrs, CT 06269.     

Novel Therapeutical Approaches to Managing Atherosclerotic Risk

Atherosclerosis is a multifactorial vascular disease that leads to inflammation and stiffening of the arteries and decreases their elasticity due to the accumulation of calcium, small dense Low Density Lipoproteins (sdLDL), inflammatory cells, and fibrotic material. A review of studies pertaining to cardiometabolic risk factors, lipids alterations, hypolipidemic agents, nutraceuticals, hypoglycaemic drugs, atherosclerosis, endothelial dysfunction, and inflammation was performed. There are several therapeutic strategies including Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitors, inclisiran, bempedoic acid, Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RAs), and nutraceuticals that promise improvement in the atheromatous plaque from a molecular point of view, because have actions on the exposure of the LDL-Receptor (LDL-R), on endothelial dysfunction, activation of macrophages, on lipid oxidation, formations on foam cells, and deposition extracellular lipids. Atheroma plaque reduction both as a result of LDL-Cholesterol (LDL-C) intensive lowering and reducing inflammation and other residual risk factors is an integral part of the management of atherosclerotic disease, and the use of valid therapeutic alternatives appear to be appealing avenues to solving the problem.     

Plasma Levels of <Emphasis Type="Italic">trans</Emphasis>-Fatty Acids are Low in Exclusively Breastfed Infants of Adolescent Mothers

The purpose of this study was to determine the levels of trans-octadecenoic acid (C18:1-trans) and trans-isomers of linoleic acid (18:2-trans), as well as long-chain polyunsaturated fatty acids (LC-PUFA), in the plasma from infants of adolescent mothers at 3 months of age, exclusively breastfed, and the relationship with the levels of the same isomers in plasma and milk of the mothers. Samples of blood and mature milk were obtained from 49 healthy adolescent mothers and their exclusively breastfed infants treated at the Instituto Fernandes Figueira-Fundação Oswaldo Cruz (IFF-FIOCRUZ) in Rio de Janeiro, Brazil. trans-Fatty acids (TFA) were analyzed by gas chromatography. The results of this study showed low levels of TFA in milk (1.53%), maternal plasma (0.50%), and plasma of infants (0.74%). The results show that, although TFA have been found in the plasma of the studied infants, the LC-PUFA levels are kept within normal limits. No association between TFA presence and parameters of nutritional status of the infants was observed, probably due to the low levels of these fatty acids found in this study.